The causes of genomic rearrangements that lead to cancer are not fully understood. It was recently suggested that a phenomenon called Break-Induced Replication (BIR) is responsible for several cancer-related events, including chromosomal translocations, loss of heterozygosity, and stabilization of chromosomal ends. All three of these events lead to cellular immortalization. BIR, a poorly understood mechanism used by cells to repair chromosomal breaks, is dangerous because it can lead to genetic rearrangements. The long-term goal of this research program is to uncover the mechanisms leading to genetic instability and, in particular, to understand the mechanism of BIR and how it is regulated by living cells to prevent genomic destabilization. The objectives of this particular application include: characterization of gross chromosomal rearrangements (GCRs) associated with repair of double-strand DNA breaks (DSBs), determining the role of BIR information of GCRs, and establishing the role of inverted DNA repeats in promoting chromosomal rearrangements. Yeast Saccharomyces cerevisiae will be used as a model eukaryotic system to study repair of DSBs. Chromosomal rearrangements will be examined by genomic microarray analysis. The physical analysis of molecular intermediates formed by inverted DNA repeats will reveal the role of these DNA motifs in promoting GCRs. The results of our proposed research will provide insights into the mechanisms of chromosomal rearrangements and the role of BIR and specific DNA motifs in promoting GCRs. Relevance. The proposed research is designed to determine the underlying cause of chromosomal aberrations that may be the mechanism for different types of cancer. This study will also identify genetic factors that predispose chromosomes to rearrangements and, therefore, will lead to improved screening procedures aimed to identify individuals who may be "at risk" for developing cancer due to abnormal patterns of DNA repair. [unreadable] [unreadable] [unreadable]